Biology subjects

Levin, J.

Publications and source records attributed to Levin, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Machine-learning MRI stratification of genetic frontotemporal dementia for clinical trial enrichment

BACKGROUNDGenetic frontotemporal dementia (FTD) shows large differences in symptom profiles, brain atrophy patterns, and progression rate, making clinical trials difficult to design and power. There is a need for biomarkers that can model disease progression, identify biologically distinct groups, and support efficient trial enrichment. METHODSWe applied contrastive trajectory inference (cTI), a machine-learning method, to structural MRI, white matter hyperintensity, and demographic data from 736 participants in the GENFI cohort, including non-carriers and carriers of C9orf72, GRN, or MAPT mutations. cTI produced an individual "genetic FTD progression score" (0-1) and grouped mutation carriers into data-driven subtypes. We tested construct validity using correlations between progression score and cognitive/functional measures, examined subtype differences in brain-behavior coupling, plasma neurofilament light (NfL), and longitudinal decline, and compared cTI-based trial enrichment against age, cortical thickness and NfL using analytic and simulation-based power analyses. RESULTSGenetic FTD progression scores correlated strongly with global dementia severity and multiple cognitive domains (all p < 0.001), confirming robust clinical scoring. Two mutation-carrier subtypes emerged: a Progressive Track (Subtype 2) with strong associations between progression score and cognitive/functional impairment, rising NfL, and faster longitudinal decline; and a Dissociated Track (Subtype 3) with comparable levels of structural variation but weak or absent clinical and NfL changes, suggesting relative biological stability. Baseline subtype membership added prognostic value for future decline in processing speed and language beyond baseline severity. Notably, for C9orf72 and GRN, cTI-informed enrichment reduced required recruited sample size per arm by about 61-75% compared with unenriched designs, and outperformed enrichment using age, cortical thickness or NfL in both analytic and simulation-based power analyses. CONCLUSIONSMachine-learning stratification of genetic FTD reveals a progressive and a dissociated disease track and provides individualized progression scores that closely track clinical status. cTI progression scores offer a powerful tool for trial enrichment, enabling smaller, more efficient prevention and early-intervention trials than conventional MRI or NfL markers alone.

neuroscience↗

bioRxiv2025

MRI-based classifier to identify close-to-onset cases in C9orf72 genetic frontotemporal dementia

Predicting symptom onset in genetic frontotemporal dementia (FTD) is crucial for advancing targeted interventions and clinical trial design. Brain changes begin years before clinical symptoms emerge, making neuroimaging a strong candidate for onset prediction. However, FTD is highly heterogeneous, encompassing diverse molecular pathologies, affected brain networks, and symptom trajectories. This variability limits the predictive power of any single imaging biomarker and underscores the need for an integrative, multimodal approach to improve prediction accuracy and generalizability. We used machine learning to integrate diverse neuroimaging features, identifying a robust signature for risk stratification. We analyzed T1-weighted and T2-weighted MRI scans from 71 symptomatic C9orf72 carriers, 90 presymptomatic carriers, and 69 healthy controls from the GENFI cohort. We used FreeSurfer to measure cortical thickness and subcortical volumes, and BISON to quantify white matter hyperintensities (WMH). We applied Principal Component Analysis for dimensionality reduction and trained a random forest classifier to distinguish symptomatic carriers from controls. The model was subsequently applied to the presymptomatic cohort to identify individuals whose brain patterns resembled those of symptomatic cases, under the hypothesis that greater similarity indicated a higher risk of conversion. We validated the model with neuropsychological data and a two-year longitudinal follow-up. The classifier distinguished symptomatic C9orf72 carriers from controls with 87.0% accuracy. When applied to presymptomatic carriers, the model identified 21.1% of the cohort as having brain features comparable to those of symptomatic cases. This "high-risk group" showed significant neuropsychological weaknesses in executive function, language and social cognition compared to the non high-risk group. The model accurately predicted clinical conversion within a two-year period with 84.5% accuracy, a 70% sensitivity and a 93.3% negative predictive value. Our findings demonstrate the utility of a machine learning approach using multi-modal MRI to identify presymptomatic C9orf72 carriers at high risk of disease onset within the next two years. By capturing subtle neuroanatomical patterns associated with disease processes, this approach offers a promising method for stratifying genetic FTD carriers prior to symptom onset. Such predictive models could optimize patient selection in future clinical trials.

neuroscience↗

bioRxiv2025

Aging-Associated Nox4-Mediated Mitochondrial ROS and DNA Damage Promote Vascular Cell Reprogramming and Aortic Remodeling in Abdominal Aneurysms

AbstractO_ST_ABSBackgroundC_ST_ABSAging and male sex are major risk factors for abdominal aortic aneurysm (AAA), a disease characterized by vascular cell phenotypic switching and aortic wall remodeling. Mitochondrial oxidative stress (mtOS) has been implicated in these changes. We previously demonstrated that NOX4 expression and activity increase with age in cardiovascular cells, promoting mtOS and vascular dysfunction. This study investigates whether NOX4-driven mtOS and DNA damage promote AAA development through vascular cell reprogramming. MethodsWe used mitochondria-targeted Nox4-overexpressing (Nox4TG) mice with an Apoe-/- background to model Angiotensin II (Ang II)-induced AAA. AAA incidence, aortic morphology, reactive oxygen species (ROS) levels, DNA damage markers, and wall remodeling parameters were assessed in Apoe-/-, Apoe-/-/Nox4TG, and Apoe-/-/Nox4-/- mice. Vascular cell populations were analyzed by spectral flow cytometry and gene expression profiling. In vitro, Ang II-treated SMCs from wild-type, Nox4TG, and Nox4-/- mice were evaluated for mtROS, DNA damage, and activation of inflammatory pathways. ResultsApoe-/-/Nox4TG mice exhibited the highest AAA incidence, aortic dilation, ROS levels, DNA damage, and inflammation, while Apoe-/-/Nox4-/- mice were most protected. Macrophage-like SMCs increased, while contractile SMCs decreased in Nox4TG aortas. Ang II-treated Nox4TG SMCs showed elevated mtROS, DNA damage, and cGAS-STING activation. Flow cytometry analysis confirmed the presence of aneurysmal SMC with reduced ACTA2, MYH11, TAGLN and increased CD68, CD11b, LGALS3 expression. ConclusionsNOX4-dependent mitochondrial DNA damage and activation of DNA- sensing pathways promote SMC phenotypic switching, inflammation, and aortic wall remodeling in AAA. Targeting NOX4 and enhancing mitochondrial function may offer therapeutic strategies for AAA prevention. CLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSO_LIThis study identifies mitochondrial NOX4-derived ROS and oxidative mitochondrial DNA damage as early and causal events in AAA pathogenesis, promoting pro-inflammatory reprogramming of vascular smooth muscle cells toward a macrophage-like phenotype. C_LIO_LIActivation of cytosolic DNA sensing (cGAS-STING) and DNase II pathways in response to mitochondrial damage links redox imbalance to innate immune activation and progressive aortic wall remodeling in AAA. C_LI What Are the Clinical Implications?O_LITargeting mitochondrial-specific oxidative stress or downstream DNA-sensing pathways offers a novel therapeutic strategy to halt AAA progression in patients with small, asymptomatic aneurysms. C_LIO_LIThese findings provide a mechanistic basis for developing mitochondria-targeted antioxidants or NOX4 inhibitors as potential pharmacologic interventions to delay or prevent AAA rupture, which could reduce the need for surgical repairs. C_LI

physiology↗

bioRxiv2025

White Matter Hyperintensities Precede other Biomarkers in GRN Frontotemporal Dementia

INTRODUCTIONIncreased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear. METHODSUsing a large dataset (n=763 GENFI2 participants), we measured WMHs and examined them across genetic FTD variants and stages. Cortical and subcortical volumes were parcellated, and serum neurofilament light chain (NfL) levels were measured. Biomarker progression was assessed with discriminative event-based and regression modeling. RESULTSSymptomatic GRN carriers showed elevated WMHs, primarily in the frontal lobe, while no significant increase was observed in C9orf72 or MAPT carriers. WMH abnormalities preceded NfL elevation, ventricular enlargement, and cortical atrophy. Longitudinally, baseline WMHs predicted subcortical changes, while subcortical volumes did not predict WMH changes, suggesting WMHs may precede neurodegeneration. DISCUSSIONWMHs are elevated in a subset of GRN-related FTD. When present, they appear early and should be considered in disease progression models. HighlightsO_LIElevated WMH volumes in symptomatic GRN carriers, but not in other mutations. C_LIO_LIWMH accumulation is mostly observed in the frontal lobe. C_LIO_LIWMH abnormalities appear early in GRN-FTD, before NfL, atrophy, and ventriculomegaly. C_LIO_LILongitudinally, WMH volumes can predict subcortical changes, but not vice versa. C_LIO_LIWMHs are key early markers in GRN-FTD and should be included in progression models. C_LI RESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSWe systematically reviewed the literature on white matter hyperintensities (WMHs) in frontotemporal dementia (FTD) using PubMed. While a few small studies reported increased WMHs in GRN mutation carriers, their sample sizes were limited, and they did not assess the timing of WMHs within disease progression or their temporal relationship to other biomarkers. InterpretationWe identified a sequence of key biomarkers in GRN-related FTD and demonstrated that WMHs are among the earliest biomarkers, preceding cortical and subcortical atrophy as well as blood biomarkers. This aligns with neuropathological evidence of early white matter involvement in FTLD-GRN. Additionally, using a larger dataset, we validated previous reports of elevated WMHs in GRN carriers, confirming their reliability. Future directionsFuture studies should integrate WMHs into FTD progression models to enhance early diagnosis. Understanding why only a subset of GRN carriers exhibit high WMH volumes remains a key research priority.

neuroscience↗

bioRxiv2024

CD388: A universally protective Drug-Fc Conjugate that targets influenza virus neuraminidase

The ability of the influenza virus to elude humoral immunity by rapid antigenic shift presents a sustained and urgent threat to human health. Globally, seasonal influenza causes an estimated 3 - 5 million cases of severe disease and 300,000 - 500,000 deaths annually, with increased potential for mortality during pandemics1. The recent outbreaks of avian H5N1 in bird populations, subsequent spread to cattle and appearance in humans, highlight the need for effective broad-spectrum influenza antivirals for treatment, prophylaxis and pandemic preparedness. The narrow, strain-specific immunity induced by current seasonal vaccines and mismatches between vaccine strains and circulating viruses result in limited vaccine effectiveness (VE) rates2. Furthermore, VE is even lower in immune-compromised and - senescent populations3. Strategies that provide durable, universal influenza protection in healthy and high-risk populations are urgently needed. Here, we describe CD388, a first-in-class antiviral drug-Fc conjugate (DFC) in clinical trials for seasonal influenza prevention (NCT05285137 and NCT05523089). CD388 comprises a multivalent small molecule inhibitor of influenza virus neuraminidase (NA) linked to a CH1-Fc hybrid domain of human IgG1 engineered for extended half-life. CD388 demonstrated potent, universal activity across influenza A and B viruses, including high pathogenicity and NA resistant strains, a low potential for resistance development, and efficacy in lethal mouse infection models. CD388 is the first therapeutic with the potential for universal prevention of influenza A and B in healthy and high-risk populations.

microbiology↗

bioRxiv2024

Neuronal and oligodendroglial but not astroglial tau translates to in vivo tau-PET signals in primary tauopathies

Tau-PET receives growing interest as an imaging biomarker for the 4-repeat tauopathy progressive supranuclear palsy (PSP). However, the translation of in vitro 4R-tau binding to in vivo tau-PET signals is still unclear. Therefore, we conducted a longitudinal [18F]PI-2620 PET/MRI study in a 4-repeat-tau mouse model (PS19) and found elevated [18F]PI-2620 PET signal in the presence of high neuronal tau. Cell sorting after radiotracer injection in vivo revealed higher tracer uptake in single neurons compared to astrocytes of PS19 mice. Regional [18F]PI-2620 tau-PET signals during lifetime correlated with abundance of fibrillary tau in subsequent autopsy samples of PSP patients and disease controls. In autoradiography, tau-positive neurons and oligodendrocytes with high AT8 density but not tau-positive astrocytes were the driver of [18F]PI-2620 autoradiography signals in PSP. In summary, neuronal and oligodendroglial tau constitutes the dominant source of tau-PET radiotracer binding in 4-repeat-tauopathies, yielding the capacity to translate to an in vivo signal.

neuroscience↗

bioRxiv2023

Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease

BackgroundThe balance between production, clearance, and toxicity of A{beta} peptides is central to Alzheimers disease (AD) pathobiology. Though highly variable in terms of age at symptom onset (AAO), hundreds of variants in PSEN1 cause autosomal dominant forms of AD (ADAD) with nearly complete penetrance. PSEN1 forms the catalytic core of the {gamma}-secretase complex and thereby directly mediates the production of longer, aggregation-prone A{beta} peptides relative to shorter, non-aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation-specific differences in the production of A{beta} species. MethodsA{beta}-37, 38, 40, 42, and 43 production was quantified from 161 unique PSEN1 variants expressed in HEK293 cells. Prediction of AAO was carried out in 106 variants with available AAO and then replicated in 55 variants represented across 190 PSEN1 mutation carriers who have detailed cognitive and biomarker data from the Dominantly Inherited Alzheimers Network (DIAN). ResultsVariations in A{beta} production across the 161 mutations examined in cell-based models were highly predictive of AAO. In those with corresponding in vivo data from the DIAN study, our cell-based {gamma}-secretase composite was strongly associated with biomarker and cognitive trajectories. ConclusionsThese findings elucidate the critical link between {gamma}-secretase function, A{beta} production, and AD progression and offer mechanistic support for the amyloid hypothesis. The approach used here represents a powerful tool to account for heterogeneity in disease progression in ADAD clinical trials and to assess the pathogenicity of variants of unknown significance or with limited family history.

neuroscience↗

bioRxiv2022

Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein

Parkinson's disease (PD) pathology progresses throughout the nervous system affecting numerous neuronal structures. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed alpha-synuclein (ASYN) on the endogenous ASYN. The appearance of the pathology in dopaminergic neurons leads to neuronal cell death and motor symptoms. However, the effect on other neuronal structures is more inconsistent, leading to a higher variability in the prevalence of non-motor symptoms. Thus, the sensitivity to the pathology seems to vary among neuronal subtypes. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology and the effect of monomeric and oligomeric ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type mice. Our results showed that pathology progression did not occur in the absence of endogenous ASYN and that dopaminergic neurons were more sensitive to ASYN and rotenone when compared to all other neuronal subtypes. Remarkably, the toxic effect of ASYN was independent of the presence of endogenous ASYN and directly related to the disturbance of the mitochondrial membrane potential. Thus, we suggest that the interaction between ASYN and mitochondria plays an important role in the toxicity of trans-synaptically transported ASYN and in the progression of PD pathology. These results question the prion-disease hypothesis and propose that endocytosed ASYN impairs the host's mitochondrial function thereby also contributing to PD-pathology progression.

neuroscience↗

bioRxiv2022

Neuroimaging within the Dominantly Inherited Alzheimer's Network (DIAN): PET and MRI

The Dominantly Inherited Alzheimer Network (DIAN) Observational Study is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). This rare form of Alzheimer disease (AD) is caused by mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. As individuals from these families have a 50% chance of inheriting the familial mutation, this provides researchers with a well-matched cohort of carriers vs non-carriers for case-control studies. An important trait of ADAD is that the age at symptom onset is highly predictable and consistent for each specific mutation, allowing researchers to estimate an individuals point in their disease time course prior to symptom onset. Although ADAD represents only a small proportion (approximately 0.1%) of all AD cases, studying this form of AD allows researchers to investigate preclinical AD and the progression of changes that occur within the brain prior to AD symptom onset. Furthermore, the young age at symptom onset (typically 30-60 years) means age-related comorbidities are much less prevalent than in sporadic AD, thereby allowing AD pathophysiology to be studied independent of these confounds. A major goal of the DIAN Observational Study is to create a global resource for AD researchers. To that end, the current manuscript provides an overview of the DIAN magnetic resonance imaging (MRI) and positron emission tomography (PET) protocols and highlights the key imaging results of this study to date.

neuroscience↗

bioRxiv2021

Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

The meninges of the brain are an important component of neuroinflammatory response. Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). However, how the calvaria bone marrow is different from the other bones and whether and how it contributes to human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific alterations including increased calvaria cell numbers. Moreover, TSPO-positron-emission-tomography imaging of stroke, multiple sclerosis and neurodegenerative disease patients demonstrate disease-associated uptake patterns in the human skull, mirroring the underlying brain inflammation. Our study indicates that the calvaria is more than a physical barrier, and its immune cells may present new ways to control brain pathologies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/473988v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@978194org.highwire.dtl.DTLVardef@bc45e8org.highwire.dtl.DTLVardef@91afdborg.highwire.dtl.DTLVardef@b06bc6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBone marrow across the mouse body display heterogeneity in their molecular profile C_LIO_LICalvaria cells have a distinct profile that is relevant to brain pathologies C_LIO_LIBrain native proteins are identified in calvaria in pathological states C_LIO_LITSPO-PET imaging of the human skull can be a proxy of neuroinflammation in the brain C_LI Supplementary Videos can be seen at: http://discotechnologies.org/Calvaria/

cell biology↗

bioRxiv2021

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

Recent studies have suggested that cerebellar and subcortical structures are impacted early in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the clinical contribution of the structures involved in the cerebello-subcortical circuitry has been understudied in FTD given their potentially central role in cognition and behaviour processes. The present study aims to investigate whether there is an association between the atrophy of the cerebellar and subcortical structures, and neuropsychiatric symptoms (using the revised version of the Cambridge Behavioral Inventory, CBI-R) across genetic mutations and whether this association starts during the preclinical phase of the disease. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative (GENFI) including mutation carriers (n=608) and non-carrier first-degree relatives of known symptomatic carriers (n= 375). Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed using deformation based morphometry (DBM) and partial least squares analyses (PLS) were used to link morphometry and behavioural symptoms. Our univariate results suggest that in this group of primarily presymptomatic subjects, volume loss in subcortical and cerebellar structure was primarily a function of aging, with only the C9orf72 group showing more pronounced volume loss in the thalamus compared to the non-carrier individuals. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to all neuropsychiatric symptoms from the CBI-R, with significant overlap in brain/behaviour patterns, but also specificity for each genetic group. The biggest differences were in the extent of the cerebellar involvement (larger extent in C9orf72 group) and more prominent amygdalar contribution in the MAPT group. Finally, our findings demonstrated that C9orf72 and MAPT brain scores were related to estimated years before the age of symptom onset (EYO) in a second order relationship highlighting a steeper brain score decline 20 years before expected symptom onset, while GRN brain scores were related to age and not EYO. Overall, these results demonstrated the important role of the subcortical structures and especially of the cerebellum in genetic FTD symptom expression.

neuroscience↗

bioRxiv2021

Global network structure and local transcriptomic vulnerability shape atrophy in sporadic and genetic behavioral variant frontotemporal dementia

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). We first identify distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbors, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicenter of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and anteromedial temporal areas. Finally, we find that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, effectively modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability.

neuroscience↗

bioRxiv2021

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.

neuroscience↗

bioRxiv2021

Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer's disease

Amyloid-beta (A{beta}) deposition is one of the hallmark pathologies in both sporadic Alzheimers disease (sAD) and autosomal dominant Alzheimers disease (ADAD), the latter of which is caused by mutations in genes involved in A{beta} processing. Despite A{beta} deposition being a centerpiece to both sAD and ADAD, some differences between these AD subtypes have been observed with respect to the spatial pattern of A{beta}. Previous work has shown that the spatial pattern of A{beta} in individuals spanning the sAD spectrum can be reproduced with high accuracy using an epidemic spreading model (ESM), which simulates the diffusion of A{beta} across neuronal connections and is constrained by individual rates of A{beta} production and clearance. However, it has not been investigated whether A{beta} deposition in the rarer ADAD can be modeled in the same way, and if so, how congruent the spreading patterns of A{beta} across sAD and ADAD are. We leverage the ESM as a data-driven approach to probe individual-level variation in the spreading patterns of A{beta} across three different large-scale imaging datasets (2 SAD, 1 ADAD). We applied the ESM separately to the Alzheimers Disease Neuroimaging initiative (N=737), the Open Access Series of Imaging Studies (N=510), and the Dominantly Inherited Alzheimers Network (N=249), the latter two of which were processed using an identical pipeline. We assessed inter- and intra-individual model performance in each dataset separately, and further identified the most likely epicenter of A{beta} spread for each individual. Using epicenters defined in previous work in sAD, the ESM provided moderate prediction of the regional pattern of A{beta} deposition across all three datasets. We further find that, while the most likely epicenter for most A{beta}-positive subjects overlaps with the default mode network, 13% of ADAD individuals were best characterized by a striatal origin of A{beta} spread. These subjects were also distinguished by being younger than ADAD subjects with a DMN A{beta} origin, despite having a similar estimated age of symptom onset. Together, our results suggest that most ADAD patients express A{beta} spreading patters similar to those of sAD, but that there may be a subset of ADAD patients with a separate, striatal phenotype.

neuroscience↗

bioRxiv2020

Functional brain age prediction suggests accelerated aging in preclinical familial Alzheimer's disease, irrespective of fibrillar amyloid-beta pathology

We aimed at developing a model able to predict brain aging from resting state functional connectivity (rs-fMRI) and assessing whether genetic risk/determinants of Alzheimers disease (AD) and amyloid (A{beta}) pathology contributes to accelerated brain aging. Using data collected in 1340 cognitively unimpaired participants from 18 to 94 years old selected across multi-site cohorts, we showed that chronological age can be predicted across the whole lifespan from topological properties of graphs constructed from rs-fMRI. We subsequently used the difference between the model-predicted age and the chronological age in pre-symptomatic autosomal dominant AD (ADAD) mutation carriers and asymptomatic individuals at risk of sporadic AD and assessed the influence of genetics and A{beta} pathology on brain age. Applying our predictive model in the context of preclinical AD revealed that the pre-symptomatic phase of ADAD is characterized by accelerated functional brain aging. This phenomenon is independent from, and might precede, detectable fibrillar A{beta} deposition.

neuroscience↗

bioRxiv2020

Loss of vacuolar acidity results in iron sulfur cluster defects and divergent homeostatic responses during aging in Saccharomyces cerevisiae

The loss of vacuolar/lysosomal acidity is an early event during aging that has been linked to mitochondrial dysfunction. However, it is unclear how loss of vacuolar acidity results in age-related dysfunction. Through unbiased genetic screens, we determined that increased iron uptake can suppress the mitochondrial respiratory deficiency phenotype of yeast vma mutants, which have lost vacuolar acidity due to genetic disruption of the vacuolar ATPase proton pump. Yeast vma mutants exhibited nuclear localization of Aft1, which turns on the iron regulon in response to iron sulfur cluster (ISC) deficiency. This led us to find that loss of vacuolar acidity with age in wildtype yeast causes ISC defects and a DNA damage response. Using microfluidics to investigate aging at the single cell level, we observe grossly divergent trajectories of iron homeostasis within an isogenic and environmentally homogeneous population. One subpopulation of cells fails to mount the expected compensatory iron regulon gene expression program, and suffers progressively severe ISC deficiency with little to no activation of the iron regulon. In contrast, other cells show robust iron regulon activity with limited ISC deficiency, which allows extended passage and survival through a period of genomic instability during aging. These divergent trajectories suggest that iron regulation and ISC homeostasis represent a possible target for aging interventions.

molecular biology↗

bioRxiv2019

Data-driven algorithm for the diagnosis of behavioral variant frontotemporal dementia

INTRODUCTIONBrain structural imaging is paramount for the diagnosis of behavioral variant of frontotemporal dementia (bvFTD), but it has low sensitivity leading to erroneous or late diagnosis. METHODSA total of 515 subjects from two different bvFTD databases (training and validation cohorts) were included to perform voxel-wise deformation-based morphometry analysis to identify regions with significant differences between bvFTD and controls. A random forest classifier was used to individually predict bvFTD from morphometric differences in isolation and together with bedside cognitive scores. RESULTSAverage ten-fold cross-validation accuracy was 89% (82% sensitivity, 93% specificity) using only MRI and 94% (89% sensitivity, 98% specificity) with the addition of semantic fluency. In a separate validation cohort of genetically confirmed bvFTD, accuracy was 88% (81% sensitivity, 92% specificity) with MRI and 91% (79% sensitivity, 96% specificity) with added cognitive scores. DISCUSSIONThe random forest classifier developed can accurately predict bvFTD at the individual subject level.

neuroscience↗

bioRxiv2019

Analysis of brain atrophy and local gene expression implicates astrocytes in Frontotemporal dementia

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of FTD, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work we combined gene expression data for 16,772 genes from the Allen Institute for Brain Science atlas with brain maps of gray matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic FTD Initiative study. No significant association was seen between (C9orf2, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. Between 1,000 and 5,000 genes showed a negative or positive correlation with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative correlation with genes involved in mitochondrial function, and a positive correlation with genes involved in vascular and glial cell function in each of the genetic groups. After adjusting for spatial autocorrelation, a set of 423 and 700 genes showed significant positive and negative correlation, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in FTD than previously assumed, and in the case of the positively-associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier respectively. Abbreviated summaryAltmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia.

neuroscience↗